Epidemic cerebrospinal meningitis (epidemic meningitis) caused by Neisseria meningitides (Nm) infection is a worldwide acute respiratory infectious disease, and may be classified into 13 serogroups depending on different capsular polysaccharide compositions of Nm. All serogroups may cause the disease, wherein, Nm diseases are mainly caused by groups A, B, C, Y, and W135, accounting for about 95% of Nm diseases, and they may cause the outbreak and of the epidemic of the diseases.
Vaccination is an economical and effective way to prevent epidemic meningitis diseases. meningococcal conjugate vaccines of different kinds and combinations have developed according to pathogenic characteristics of their epidemic meningitis bacteria, in various countries in the world, including capsular polysaccharide vaccines for group A, group C, groups A and C, and groups A, C, Y and W135, and polysaccharide-protein conjugate vaccines for group A, group C, groups A and C, and groups A, C, Y and W135 having tetanus toxoid (TT), diphtheria toxoid (DT), or non-toxic mutant of diphtheria toxin (CRM197) as a carrier protein. The examples of meningococcal vaccines for group B are VA-MENGOC-BC vaccine produced by Cuban Finlay Institute, which contains B group OMV, C group CPS (capsular polysaccharide) and adjuvant AL (OH)3, and Novartis 4C Men B (Bexsero) vaccine containing fHbp type I protein, Nad A protein and protein NHBA, and New Zealand group B OMV vaccine (MeNZB).
At present, for meningococcal polysaccharide-protein conjugate vaccines that are being developed at home and abroad or already in the market, the carrier protein used is non-toxic mutant of diphtheria toxin (CRM197), tetanus toxoid (TT) or diphtheria toxoid (DT). Although these carrier proteins also may stimulate the organism to produce corresponding antibodies, the antibodies are irrelevant to the prevention of meningococcal diseases and merely have a carrier effect. Moreover, TT and DT are obtained by detoxication of corresponding bacterial toxins with formaldehyde or glutaraldehyde and in the application of Pertussis-Diphtheria-Tetanus triple vaccine, in order to avoid toxicity reversion, it is necessary to add trace formaldehyde or glutaraldehyde to maintain stability of the detoxication effect. However, formaldehyde and glutaraldehyde are not added to conjugate vaccines having TT or DT as a carrier protein, there is thus a risk of the toxicity reversion of the carrier protein. Moreover, tetanus toxoid is a hyperallergenic substance, and it is difficult to completely avoid safety risks including “anaphylaxis” and the like in vaccination of polysaccharide-protein conjugate vaccines having tetanus toxoid (TT) or diphtheria toxoid (DT) as a carrier protein, caused by unthorough detoxication.
In case of vaccination of multivalent polysaccharide conjugate vaccines having a single carrier protein, it is difficult to completely avoid a phenomenon of competition between antigenic sites in the vaccinated organism. As the amount of T cells specific for a same carrier in the vaccinated organism is limited, there is competitive inhibition between various polysaccharide conjugates of the single carrier and thus some antigens may not find corresponding binding sites, thereby decreasing the immunization effect. This phenomenon is called “competition between antigenic sites”. It is reported in literatures that TT-induced epitope inhibition is more obvious.
Additionally, only a single carrier protein is used in a multivalent polysaccharide-protein conjugate vaccine, and the kinds of the carrier protein are unitary, leading to a too large vaccination dosage of the carrier protein at each vaccination. Thereby, after repeated vaccination of large amount of carrier proteins, immune tolerance against the carrier protein is formed, affecting immunogenicity of polysaccharides binding to the carrier protein and resulting in decreased immune response. This phenomenon is called “immune tolerance”. It has attracted concern and attention of domestic and foreign scholars.
Hence, it is necessary to develop a vaccine that may effectively prevent infectious diseases caused by Neisseria meningitides groups A, C, Y and W135.